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Huwe1 Regulates the Establishment and Maintenance of Spermatogonia by Suppressing DNA Damage Response.

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机构： [1]Department of Medicine, McGill University and McGill University Health Centre Research Institute,Montreal, Quebec H4A 3J1, Canada [2]Epithelial Cell Biology Research Center, School of Biomedical Sciences,Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong [3]Department of Obstetrics andGynecology, McGill University and McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada [4]Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine,Sichuan University, Chengdu, Sichuan 610041, China [5]Institute for Cancer Genetics, Columbia UniversityMedical Center, New York, New York 10032 [6]Department of Biochemistry, McGill University, Montreal,Quebec H3G 1Y6, Canada [7]Department of Obstetrics and Gynecology, West China Second UniversityHospital, Sichuan University, Chengdu, Sichuan 610041, China

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Spermatogenesis is sustained by a heterogeneous population of spermatogonia that includes the spermatogonial stem cells. However, the mechanisms underlying their establishment from gonocyte embryonic precursors and their maintenance thereafter remain largely unknown. In this study, we report that inactivation of the ubiquitin ligase Huwe1 in male germ cells in mice led to the degeneration of spermatogonia in neonates and resulted in a Sertoli cell-only phenotype in the adult. Huwe1 knockout gonocytes showed a decrease in mitotic re-entry, which inhibited their transition to spermatogonia. Inactivation of Huwe1 in primary spermatogonial culture or the C18-4 cell line resulted in cell degeneration. Degeneration of Huwe1 knockout spermatogonia was associated with an increased level of histone H2AX and an elevated DNA damage response that led to apparent mitotic catastrophe but not apoptosis or senescence. Blocking this increase in H2AX prevented the degeneration of Huwe1-depleted cells. Taken together, these results reveal a previously undefined role of Huwe1 in orchestrating the physiological DNA damage response in the male germline that contributes to the establishment and maintenance of spermatogonia. Copyright © 2017 Endocrine Society.

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出版当年[2017]版：

大类 | 2 区

医学

小类 | 2 区内分泌学与代谢

最新[2023]版：

大类 | 3 区医学

小类 | 3 区内分泌学与代谢

第一作者：

第一作者机构： [1]Department of Medicine, McGill University and McGill University Health Centre Research Institute,Montreal, Quebec H4A 3J1, Canada [2]Epithelial Cell Biology Research Center, School of Biomedical Sciences,Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong

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通讯机构： [1]Department of Medicine, McGill University and McGill University Health Centre Research Institute,Montreal, Quebec H4A 3J1, Canada [4]Sichuan University–The Chinese University of Hong Kong Joint Laboratory for Reproductive Medicine,Sichuan University, Chengdu, Sichuan 610041, China [7]Department of Obstetrics and Gynecology, West China Second UniversityHospital, Sichuan University, Chengdu, Sichuan 610041, China [*1]McGill University Health Centre Research Institute, 1001 D´ecarie Boulevard, Room E02.7232, Montreal, Quebec H4A 3J1, Canada. [*2]The Joint Laboratory for Reproductive Medicine, SCU-CUHK, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China

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